胸腺素β10在脑胶质瘤中表达及其临床意义
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摘要
目的:分析胸腺素β10(thymosinβ10,TMSB10)在脑胶质瘤中的表达特征及其临床意义,并探讨其参与脑胶质瘤发生和发展的生物学过程。方法:收集2004年—2017年北京天坛医院和北京三博脑科医院收治的胶质瘤患者339例,其中309例肿瘤组织标本用于中国脑胶质瘤基因组图谱计划(Chinese Glioma Genome Atlas,CGGA)mRNA测序数据库构建,另外30例组织标本用于实时荧光定量PCR以验证TMSB10 mRNA表达情况。分析CGGA数据库中TMSB10 mRNA表达与309例脑胶质瘤患者临床资料的相关性,并用TCGA数据库的mRNA测序数据和REMBRANDT数据库的mRNA芯片数据进行同步验证。采用方差分析法和t检验分析TMSB10在不同病理级别、分子亚型中的表达特征。采用Kaplan-Meier法、log-rank检验和COX回归模型分析TMSB10表达与脑胶质瘤患者生存期的关系,χ2检验分析TMSB10表达与脑胶质瘤多项临床指标的关系。采用Pearson相关性检验和DAVID分析探究TMSB10表达相关基因参与的生物学过程。结果:随着脑胶质瘤病理级别升高,TMSB10 mRNA表达水平明显升高(P<0.000 1);TMSB10在恶性程度较高的间质型和异柠檬酸脱氢酶野生型脑胶质瘤中表达水平更高(P值均<0.000 1);而且TMSB10高表达的脑胶质瘤患者总生存期明显短于TMSB10低表达患者(P<0.000 1)。TMSB10表达是一个与脑胶质瘤患者总生存期有关的独立预测因子(P<0.05)。TMSB10可能与脑胶质瘤的免疫反应、细胞黏附、血管生成、炎性反应和细胞凋亡等生物学过程有关。结论:TMSB10是促进脑胶质瘤发生和发展的潜在因素之一,可作为判断患者预后的一个潜在指标。
Objective: To analyze the expression and clinical significance of thymosin β10(TMSB10) in gliomas, and to explore its biological processes involved in the occurrence and development of gliomas.Methods: A total of 339 glioma samples were collected from Beijing Tian Tan Hospital and Beijing Sanbo Brain Hospital from 2004 to 2017. Among them, 309 samples were used for the construction of the Chinese Glioma Genome Altas(CGGA) mRNA sequencing database,and 30 other samples were used for real-time fl uorescence quantitative PCR to verify TMSB10 mRNA expression. The correlation of TMSB10 mRNA expression in the CGGA database with the clinical data of 309 glioma patients was analyzed, and the TCGA mRNA sequencing data and the REMBRANDT mRNA microarray data were simultaneously used for verification. The expression of TMSB10 in different pathological grades and molecular subtypes of gliomas was analyzed by ANOVA and t test. The relationship of TMSB10 expression and the overall survival of glioma patients was analyzed by Kaplan-Meier method, log-rank test and COX regression model. The relationship between the expression of TMSB10 and the several pathological factors of glioma was analyzed by chi-square test. The biological processes involved in TMSB10 expression were analyzed by Pearson correlation test and DAVID.Results: The expression level of TMSB10 in high-grade gliomas was significantly higher than that in low-grade gliomas(P < 0.000 1). The expression level of TMSB10 was higher in mesenchymal and isocitrate dehydrogenase(IDH) wild-type gliomas(both P < 0.000 1).The overall survival rate of patients with high expression of TMSB10 was significantly lower than that of patients with low expression of TMSB10(P < 0.000 1). Moreover, TMSB10 was an independent prognostic factor related to overall survival for the patients with glioma(P < 0.05).TMSB10 might be associated with the biological process of glioma such as immune response,cell adhesion, angiogenesis, inflammatory reaction and apoptosis.Conclusion: TMSB10 is one of potential factors to promote the occurrence and development of glioma, and can be used as a potential indicator to predict the prognosis of glioma patients.
Objective: To analyze the expression and clinical significance of thymosin β10(TMSB10) in gliomas, and to explore its biological processes involved in the occurrence and development of gliomas.Methods: A total of 339 glioma samples were collected from Beijing Tian Tan Hospital and Beijing Sanbo Brain Hospital from 2004 to 2017. Among them, 309 samples were used for the construction of the Chinese Glioma Genome Altas(CGGA) mRNA sequencing database,and 30 other samples were used for real-time fl uorescence quantitative PCR to verify TMSB10 mRNA expression. The correlation of TMSB10 mRNA expression in the CGGA database with the clinical data of 309 glioma patients was analyzed, and the TCGA mRNA sequencing data and the REMBRANDT mRNA microarray data were simultaneously used for verification. The expression of TMSB10 in different pathological grades and molecular subtypes of gliomas was analyzed by ANOVA and t test. The relationship of TMSB10 expression and the overall survival of glioma patients was analyzed by Kaplan-Meier method, log-rank test and COX regression model. The relationship between the expression of TMSB10 and the several pathological factors of glioma was analyzed by chi-square test. The biological processes involved in TMSB10 expression were analyzed by Pearson correlation test and DAVID.Results: The expression level of TMSB10 in high-grade gliomas was significantly higher than that in low-grade gliomas(P < 0.000 1). The expression level of TMSB10 was higher in mesenchymal and isocitrate dehydrogenase(IDH) wild-type gliomas(both P < 0.000 1).The overall survival rate of patients with high expression of TMSB10 was significantly lower than that of patients with low expression of TMSB10(P < 0.000 1). Moreover, TMSB10 was an independent prognostic factor related to overall survival for the patients with glioma(P < 0.05).TMSB10 might be associated with the biological process of glioma such as immune response,cell adhesion, angiogenesis, inflammatory reaction and apoptosis.Conclusion: TMSB10 is one of potential factors to promote the occurrence and development of glioma, and can be used as a potential indicator to predict the prognosis of glioma patients.
引文
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[15]李紫璇,曲连悦,钟红珊,等.胸腺素β10在人肺腺癌细胞株A549中抑制细胞凋亡、促进细胞增殖机制研究[J].中国肺癌杂志,2014,17(11):783-788.
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[22]TSUJI M,MONKAWA T,YOSHINO J,et al.Microarray analysis of a reversible model and an irreversible model of anti-Thy-1 nephritis[J].Kidney Int,2006,69(6):996-1004.
[23]LAPTEVA N,ANDO Y,NIEDA M,et al.Profiling of genes expressed in human monocytes and monocyte-derived dendritic cells using cDNA expression array[J].Br J Haematol,2001,114(1):191-197.
[24]GUTIERREZ-PABELLO JA,MCMURRAY DN,ADAMS LG.Upregulation of thymosin beta-10 by Mycobacterium bovis infection of bovine macrophages is associated with apoptosis[J].Infect Immun,2002,70(4):2121-2127.
[2]HANNAPPEL E.beta-Thymosins[J].Ann N Y Acad Sci,2007,1112:21-37.
[3]SALHAB M,PAPILLIER P,PERREAU C,et al.Thymosins beta-4 and beta-10 are expressed in bovine ovarian follicles and upregulated in cumulus cells during meiotic maturation[J].Reprod Fertil Dev,2010,22(8):1206-1221.
[4]刘从容,马春树,宁钧宇,等.不同转移潜能肿瘤细胞胸腺素β10表达水平及微丝结构的差异性研究[J].中华病理学杂志,2004,33(1):67-71.
[5]YU FX,LIN SC,MORRISON-BOGORAD M,et al.Thymosin beta 10 and thymosin beta 4 are both actin monomer sequestering proteins[J].J Biol Chem,1993,268(1):502-509.
[6]WIRSCHING HG,KRISHNAN S,FLOREA AM,et al.Thymosin beta 4 gene silencing decreases stemness and invasiveness in glioblastoma[J].Brain,2014,137(Pt 2):433-448.
[7]VERGHEE-NIKOLAKAKIS,APOSTOLIKAS N,LIVANIOU E,et al.Preliminary findings on the expression of thymosin beta-10 in human breast cancer[J].Br J Cancer,1996,74(9):1441-1444.
[8]OIEN KA,VASS JK,DOWNIE I,et al.Profiling,comparison and validation of gene expression in gastric carcinoma and normal stomach[J].Oncogene,2003,22(27):4287-4300.
[9]SARDI I,TINTORI V,MARCHI C,et al.Molecular profiling of high-risk neuroblastoma by cDNA array[J].Int J Mol Med,2002,9(5):541-545.
[10]VERHAAK RG,HOADLEY KA,PURDOM E,et al.Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA,IDH1,EGFR,and NF1[J].Cancer Cell,2010,17(1):98-110.
[11]YAN H,PARSONS DW,JIN G,et al.IDH1 and IDH2 mutations in gliomas[J].N Engl J Med,2009,360(8):765-773.
[12]SRIBENJAS,SAWANYAWISUK,KRAIKLANG R,et al.Suppression of thymosin beta10 increases cell migration and metastasis of cholangiocarcinoma[J].BMC Cancer,2013,13:430.
[13]CALIFANO D,MONACO C,SANTELLI G,et al.Thymosin beta-10 gene over-expression correlated with the highly malignant neoplastic phenotype of transformed thyroid cells in vivo and in vitro[J].Cancer Res,1998,58(4):823-828.
[14]WETERMAN MA,VAN MUIJEN GN,RUITER DJ,et al.Thymosin beta-10 expression in melanoma cell lines and melanocytic lesions:a new progression marker for human cutaneous melanoma[J].Int J Cancer,1993,53(2):278-284.
[15]李紫璇,曲连悦,钟红珊,等.胸腺素β10在人肺腺癌细胞株A549中抑制细胞凋亡、促进细胞增殖机制研究[J].中国肺癌杂志,2014,17(11):783-788.
[16]KIM YC,KIM BG,LEE JH.Thymosin beta10expression driven by the human TERT promoter induces ovarian cancer-specific apoptosis through ROS production[J].PLoS One,2012,7(5):e35399.
[17]ANADONR,RODRIGU EZMOLDE SI,CARPINTERO P,et al.Differential expression of thymosins beta(4)and beta(10)during rat cerebellum postnatal development[J].Brain Res,2001,894(2):255-265.
[18]CARPINTERO P,ANADON R,GOMEZMARQUEZ J.Expression of the thymosin beta10 gene in normal and kainic acid-treated rat forebrain[J].Brain Res Mol Brain Res,1999,70(1):141-146.
[19]HALL AK.Developmental regulation of thymosin beta 10 mRNA in the human brain[J].Brain Res Mol Brain Res,1991,9(1/2):175-177.
[20]NAKANISHI F,OHKAWA K,ISHIDA H,et al.Alteration in gene expression profile by fulllength hepatitis B virus genome[J].Intervirology,2005,48(2/3):77-83.
[21]KA SM,RIFAI A,CHEN JH,et al.Glomerular crescent-related biomarkers in a murine model of chronic graft versus host disease[J].Nephrol Dial Transplant,2006,21(2):288-298.
[22]TSUJI M,MONKAWA T,YOSHINO J,et al.Microarray analysis of a reversible model and an irreversible model of anti-Thy-1 nephritis[J].Kidney Int,2006,69(6):996-1004.
[23]LAPTEVA N,ANDO Y,NIEDA M,et al.Profiling of genes expressed in human monocytes and monocyte-derived dendritic cells using cDNA expression array[J].Br J Haematol,2001,114(1):191-197.
[24]GUTIERREZ-PABELLO JA,MCMURRAY DN,ADAMS LG.Upregulation of thymosin beta-10 by Mycobacterium bovis infection of bovine macrophages is associated with apoptosis[J].Infect Immun,2002,70(4):2121-2127.